Impact of distal aortic and visceral perfusion on liver function during thoracoabdominal and descending thoracic aortic repair

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1 ORIGINAL ARTICLES Impact of distal aortic and visceral perfusion on liver function during thoracoabdominal and descending thoracic aortic repair Hazim J. Safi, MD, Charles C. Miller III, PhD, David H. Yawn, MD, Dimitrious C. Iliopoulos, MD, Mahesh Subramaniam, MS, Stuart Harlin, MD, and George V. Letsou, MD, Houston, Tex. Purpose: We examined the impact of distal aortic and visceral perfusion on liver function during thoracoabdominal and descending thoracic aortic repair. Methods: Between January 1991 and July 1996, 367 patients underwent thoracoabdominal and descending thoracic aortic repair. Baseline and postoperative total bilirubin, alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, lactate dehydrogenase, fibrinogen, prothrombin time (PT), and partial thromboplastin time (PTT) were measured for 286 patients. We examined the impact of distal aortic and direct visceral perfusion on liver function related clinical laboratory values. Univariate and multivariate statistical methods for categorical and continuous variables were used. Results: In categorical analysis, type II thoracoabdominal aortic aneurysm, history of hepatitis, and emergency presentation had a statistically significant multivariate association with abnormal laboratory values. In continuous-distributed multivariate data analysis, type II thoracoabdominal aortic aneurysm and visceral perfusion were statistically significant predictors of postoperative alkaline phosphatase, PT, and PTT. Type II aneurysms increased postoperative liver function related laboratory values significantly above other aneurysm types (alkaline phosphatase, +114 IU, p < ; PT, seconds, p < 0.02; PTT, +6.7 seconds, p < 0.03). Visceral perfusion was associated with a concomitant decrease (alkaline phosphatase, IU, p < ; PT, 1.8 seconds, p < 0.07; PTT, 5.6 seconds, p < 0.02). Conclusions: Visceral perfusion negates the rise in postoperative liver function related clinical laboratory values associated with type II thoracoabdominal aortic aneurysm repair. (J Vasc Surg 1998;27: ) The complex repair of thoracoabdominal and descending thoracic aortic aneurysms requires interruption of blood flow in the arterial system s central conduit. Interruption of circulation may cause prolonged ischemia and associated end-organ damage. As surgical technique has evolved, several adjuncts From Baylor College of Medicine, Methodist Hospital. Presented at the Twenty-first Annual Meeting of The Southern Association for Vascular Surgery, Coronado, Calif., Jan , Reprint requests: Hazim J. Safi, MD, Baylor College of Medicine, The Methodist Hospital, 6550 Fannin, Suite 1603, Houston, TX Copyright 1998 by The Society for Vascular Surgery and International Society for Cardiovascular Surgery, North American Chapter /98/$ /6/85836 have been described that minimize ischemic time and aid in organ preservation. We have previously examined the factors implicated in postoperative injury of the heart, spinal cord, kidneys, and lungs and have explored possible methods to avoid such complications. In this article we focus on the reduction of insult to the liver during thoracoabdominal and descending thoracic aortic aneurysm repair. Ischemia is a well-documented source of hepatic injury, and ischemic hepatitis is known to cause elevation of enzyme levels. 1-4 No single test or procedure can measure the total function of the liver because it is involved in nearly every metabolic process in the body. In this study we did not attempt to diagnose liver disease but instead used a variety of laboratory and statistical tests to identify hepatic insult and also to identify risk factors for 145

2 146 Safi et al. January 1998 Table I. Patient characteristics Variable No. of patients (%) No. of abnormal test results (%) Odds ratio* 95% CI p All patients 286 (100.0) 35 (12.2) Age (75.2) 28 (13.0) to Age < (24.8) 7 (9.9) 1 Female 106 (37.1) 15 (14.2) to Male 180 (63.9) 20 (11.1) 1 Hypertensive 220 (76.9) 31 (14.1) to Otherwise 66 (23.1) 4 (6.1) 1 Smoker 110 (38.5) 16 (14.6) to Nonsmoker 176 (61.5) 19 (10.8) 1 Renal insufficiency 55 (19.2) 6 (10.9) to Otherwise 231 (80.8) 29 (12.6) 1 COPD 85 (29.7) 12 (14.1) to Otherwise 201 (70.3) 23 (11.4) 1 Cerebrovascular disease 34 (11.9) 5 (14.7) to Otherwise 252 (88.1) 30 (11.9) 1 Diabetes 26 (9.1) 3 (11.5) to Otherwise 260 (90.9) 32 (12.3) 1 History of hepatitis 8 (2.8) 3 (37.5) to Otherwise 278 (97.2) 32 (11.5) 1 TAAA I 90 (31.5) 5 (5.6) to Otherwise 196 (68.5) 30 (15.3) 1 TAAA II 100 (34.9) 21 (21.0) to Otherwise 186 (65.1) 14 (7.5) 1 TAAA III 33 (11.5) 4 (12.1) to Otherwise 253 (88.5) 31 (12.3) 1 TAAA IV 27 (9.4) 3 (11.1) to Otherwise 259 (90.6) 32 (12.4) 1 Acute dissection 13 (4.6) 1 (7.7) to Otherwise 273 (95.4) 34 (12.5) 1 Rupture 17 (5.9) 6 (35.3) to Otherwise 269 (94.1) 29 (10.8) 1 Emergency 23 (8.0) 8 (34.8) to Otherwise 263 (92.0) 27 (10.3) 1 Adjunct 174 (60.9) 21 (12.1) to Otherwise 112 (39.2) 14 (12.5) 1 Distal perfusion 116 (62.4) 8 (6.9) to Otherwise 70 (37.6) 6 (8.6) 1 Visceral perfusion 80 (80.0) 15 (18.8) to Otherwise 20 (20.0) 6 (30.0) 1 Abnormal laboratory values were considered to be present if any one of AST, ALT, LDH, alkaline phosphatase, PT, or PTT were greater than 4 times top normal for our laboratory, or total bilirubin was greater than 10. Adjunct use (distal aortic perfusion + cerebrospinal fluid drainage) is shown for all aneurysm types. Distal aortic perfusion alone is shown for non type II aneurysms. Visceral perfusion, which can be performed only when visceral vessel aortic insertions are exposed, is shown only for patients with type II aneurysms. CI, Confidence interval; COPD, chronic obstructive pulmonary disease; TAAA I to IV, thoracoabdominal aortic aneurysm Crawford class I, II, III, or IV. *Odds ratio represents a test against a reference category whose referent odds ratio is equal to 1. 95% CI reflects the units against which its companion odds ratio is computed. Confidence intervals are test-based. p is the probability of a type I statistical error (common p value). Values are Pearson c 2 probabilities. Type I, III, IV, and descending aneurysms only (n = 186). Type II aneurysms only. such insult that may be amenable to modification through refinements in surgical technique. We report a comparison of baseline to postoperative enzyme measurements used to determine the impact of visceral and distal perfusion on liver function after thoracoabdominal and descending thoracic aortic repair.

3 Volume 27, Number 1 Safi et al. 147 Fig. 1. Visceral perfusion of celiac axis, superior mesenteric artery, and renal arteries. Fig. 2. Depiction of linear regression equation shown in Table IV for AST. Solid line represents relationship between preoperative and postoperative variables for type I, III, IV, and descending thoracic aneurysms. Line with short dashes represents this relationship for type II aneurysms without visceral perfusion. Long-dashed line represents relationship in type II patients who received visceral perfusion during operation. Type II aneurysm extent is associated with upward shift in postoperative variable values, whereas use of visceral perfusion brings relationship back to essentially that of other aneurysm types. PATIENTS AND METHODS Patients. Between January 1991 and July 1996, we performed thoracoabdominal or descending thoracic aortic aneurysm repair in 367 patients. Baseline and postoperative total bilirubin, alanine aminotransferase (ALT or SGPT), aspartate aminotransferase (AST or SGOT), alkaline phosphatase, lactate dehydrogenase (LDH), fibrinogen, prothrombin time (PT), and partial thromboplastin time (PTT) were measured for 286 patients. We examined the impact of distal and visceral perfusion on liver function as compared with simple cross-clamp technique. Postoperative values analyzed were the highest values recorded in the interval between awakening from anesthesia and discharge from the hospital. Table I describes the pertinent characteristics of the study population. Surgical technique. The majority of patients (174; 61%) underwent thoracoabdominal and descending thoracic aortic graft replacement with cerebral spinal fluid drainage, distal aortic perfusion, and moderate hypothermia, with reattachment of intercostal arteries, which we have described at length previously. 5 For pump cases, all patient types received distal aortic perfusion. For the most extensive aneurysms thoracoabdominal type II direct perfusion of the visceral arteries was begun as illustrated in Fig. 1 when the distal aneurysm was opened. Although repair of some other aneurysm types (III and IV) involves exposure of the visceral arteries, we do not perfuse these arteries directly because of the relatively short time required to perform such repairs. Sixty-seven (23%) patients underwent graft replacement without adjuncts using the simple cross-clamp technique. Cross-clamping and graft replacement was performed in segmental and sequential fashion. For pump cases, after induction of anesthesia a 14-gauge Tuohy needle was inserted in the intervertebral space between L3 and L4 for cerebral spinal fluid drainage, and the chest was opened through a left thoracoabdominal incision through the sixth intercostal space. The sixth rib was removed. A catheter for distal aortic perfusion was placed in the left common femoral artery after a left groin incision, and the left atrial appendage was cannulated for the venous portion of cardiofemoral bypass after the pericardium was opened, posterior to the left phrenic nerve. The initial placement of clamps was just distal to the left subclavian artery and at the

4 148 Safi et al. January 1998 Table II. Multiple logistic regression model Variable Parameter estimate Standard error Adjusted odds ratio 95% CI p Intercept TAAA II to History of hepatitis to Emergency case to CI, Confidence interval; TAAA II, thoracoabdominal aortic aneurysm. Table III. Effect of abnormal laboratory value threshold on associations between risk factors and outcomes Variable No. 2 top Odds 4 top Odds normal criterion ratio p normal criterion ratio p All patients (25.9) 35 (12.2) History of hepatitis 8 4 (50.0) (37.5) Otherwise (25.2) 1 32 (11.5) 1 Renal insufficiency (38.2) (10.9) Otherwise (22.9) 1 29 (12.6) 1 Diabetes (42.3) (11.5) Otherwise (24.2) 1 32 (12.3) 1 TAAA II (40.0) (21.0) Otherwise (18.3) 1 14 (7.5) 1 Rupture 17 8 (47.1) (35.3) Otherwise (24.5) 1 29 (10.8) 1 Emergency (60.9) (34.8) Otherwise (22.8) 1 27 (10.3) 1 Visceral perfusion* (38.8) (18.8) Otherwise 20 9 (45.0) 1 6 (30.0) 1 TAAA II, Thoracoabdominal aortic aneurysm type II. *Type II aneurysms only. mid-descending aorta. After proximal anastomosis of the graft to the descending thoracic aorta, the distal clamp was moved to the infrarenal abdominal aorta. The remainder of the aneurysm was then opened. Visceral perfusion of the celiac axis, superior mesenteric artery, and right and left renal arteries for thoracoabdominal aortic aneurysm type II was via #9 Pruitt catheter. The rate of flow to the visceral arteries depended on proximal aortic pressure and ranged from 200 to 600 ml/min. Finally, after reattachment of the intercostal and visceral arteries, the distal anastomosis was performed. Statistical methods. For the categorical analyses that pertain to Tables I and II, an indicator variable for abnormal results was set to 1 if any of the laboratory values of alkaline phosphatase, LDH, AST, ALT, PT, or PTT was greater than four times the upper limit of the normal range, or if total bilirubin was greater than 10. For the analyses pertinent to Table III, two criteria for abnormal laboratory results were compared. One considered anything above four times the upper limit of the normal range to be abnormal as described above (4 top normal), and the other considered two times the upper limit of the normal range to be abnormal (2 top normal). Univariate frequency analysis was conducted using contingency table tests, and multivariate frequency analysis was performed using multiple logistic regression. Linear regression models were used to evaluate the effects of aneurysm extent and distal and visceral perfusion on postoperative laboratory values expressed as continuous variables. All computations were performed using SAS software version Visceral perfusion was only used in type II thoracoabdominal aortic aneurysm repairs as described above. In contingency table analysis, evaluation of visceral perfusion was confined to type II cases, where it was actually applied. In the linear regression analyses, an indicator variable for visceral perfusion was applied to the entire population. RESULTS The univariate relationships between patient characteristics and one or more abnormal liver function related laboratory values are shown in Table I.

5 Volume 27, Number 1 Safi et al. 149 Table IV. Determinants of postoperative laboratory values multiple linear regression models Variable Parameter estimate Partial R 2 p Postoperative alkaline phosphatase Intercept Preoperative alkaline phosphatase TAAA II Visceral perfusion Postoperative AST Intercept Preoperative AST TAAA II Visceral perfusion Postoperative PT Intercept Preoperative PT TAAA II Visceral perfusion Postoperative PTT Intercept Preoperative PTT TAAA II Visceral perfusion Postoperative AST (interaction model) Intercept Preoperative AST TAAA II Visceral perfusion AST + TAAA II AST + visceral perfusion Multiple linear regression analysis of influence of baseline variable values, aneurysm type, and use of visceral perfusion on postoperative variable values. Partial R 2 is the proportion of variance in postoperative values accounted for by each explanatory variable. Partial R 2 is calculated using type II sums of squares, which present each statistic as though it were included as the final term in the model. Parameter estimates for preoperative variables represent the average change in postoperative value for each one-unit change in preoperative value. Parameter estimates for TAAA II and visceral perfusion indicate the average change in postoperative variable value that is associated with the presence of the predictors. Note that use of visceral perfusion reduces the average postoperative value by approximately the amount that the postoperative value is increased by type II aneurysm. TAAA II, Thoracoabdominal aortic aneurysm type II Abnormal liver function, presented in Table I, is defined by the 4 top normal criterion described in the Methods section above. Overall, 35 patients had laboratory abnormalities by this criterion. Significant univariate predictors were history of hepatitis, type II aortic aneurysm, ruptured aortic aneurysm, and emergency presentation. Table II shows a multiple logistic regression analysis that demonstrates the significant independent effects of type II aneurysm, history of hepatitis, and emergency presentation on the probability of having abnormal postoperative liver-related laboratory results. Table III shows the effect of abnormal laboratory value threshold on univariate associations between risk factors and abnormal laboratory results. On the left hand side of the table, laboratory values greater than 2 top normal are considered abnormal. On the right side, values greater than 4 top normal are considered abnormal. With the 2 criterion, renal insufficiency, diabetes, type II aneurysm, rupture, emergency presentation, and intraoperative perfusion of the visceral arteries are significantly associated with laboratory abnormalities. With the 4 criterion, history of hepatitis, type II aneurysm, ruptured aneurysm, emergency presentation, and use of visceral perfusion are significantly associated with abnormal laboratory values. The last row of Table III shows visceral perfusion confined only to type II aneurysms the type of aneurysm repair for which it was used. Although not statistically significant (probably because of small numbers of events), visceral perfusion appears to mitigate the effects of type II aneurysm. This conclusion is borne out by statistically significant data shown in Table IV. Table IV shows the results of multiple linear regression analyses for individual postoperative laboratory values. Laboratory tests that had at least one significant predictor are included in the table. In general, the strongest predictor for each postoperative laboratory value was the baseline value of that same variable. For alkaline phosphatase, the preoperative value, type II aneurysm, and visceral perfusion were all highly significant predictors. For

6 150 Safi et al. January 1998 Fig. 3. Depiction of linear regression equation shown in Table IV for alkaline phosphatase. Solid line represents relationship between preoperative and postoperative variables for type I, III, IV, and descending thoracic aneurysms. Line with short dashes represents this relationship for type II aneurysms without visceral perfusion. Long-dashed line represents relationship in type II patients who received visceral perfusion during operation. Type II aneurysm extent is associated with upward shift in postoperative variable values, whereas use of visceral perfusion brings relationship back to essentially that of other aneurysm types. AST, only the baseline value was predictive. For PT, baseline value and type II aneurysm were significant, with visceral perfusion narrowly missing statistical significance. For PTT, baseline value, type II aneurysm, and visceral perfusion were all significant predictors. For all laboratory tests, visceral perfusion decreased the postoperative value by approximately the same amount as type II aneurysm increased that value (Figs. 2 through 5). DISCUSSION Complex repair of the thoracoabdominal aorta exposes patients to ischemic insult and puts them at risk for end-organ damage. We found that gross correlates of ischemia, such as rupture and emergency presentation, were significant predictors of liver function abnormalities for all patients. Thoracoabdominal aortic aneurysm type II, of all aneurysm types, is the most complex to repair and carries the longest total ischemic time. In this series, the prevalence of postoperative liver dysfunction was highest in patients with type II aneurysms. In many previous studies, this type of aneurysm has been shown to be associated with neurologic, renal, and pulmonary Fig. 4. Depiction of linear regression equation shown in Table IV for PT. Solid line represents relationship between preoperative and postoperative variables for type I, III, IV, and descending thoracic aneurysms. Line with short dashes represents this relationship for type II aneurysms without visceral perfusion. Long-dashed line represents relationship in type II patients who received visceral perfusion during operation. Type II aneurysm extent is associated with upward shift in postoperative variable values, whereas use of visceral perfusion brings relationship back to essentially that of other aneurysm types. complications, as well as a diminished long-term survival rate Liver dysfunction is difficult to study because the diagnosis is made clinically, so that definitive criteria for diagnosing liver disease from retrospective data do not exist. Despite the difficulty of diagnosis, however, practical measurements of clinical laboratory values can be used to study hepatic insult after surgery. Bilirubin results from the metabolism of heme in the tissues. The liver conjugates the pigment and excretes it against an energy-dependent gradient in the bile. Elevated serum bilirubin can result from a wide variety of acquired and congenital disorders, and hepatic ischemia has been reported to cause hyperbilirubinemia. Alkaline phosphatase is a widespread enzyme found in especially high concentrations in the intestines, kidneys, bone, liver, and placenta. In normal adults the liver is a major source of the serum concentrations of this enzyme. LDH, like alkaline phosphatase, is widely distributed in the liver, red blood cells, and skeletal and cardiac muscle. Biliary obstruction and intrahepatic cholestasis can cause elevations of this enzyme. Hepatic parenchymal cell injury usually causes only a twofold to threefold elevation of alka-

7 Volume 27, Number 1 Safi et al. 151 line phosphatase. Alanine aminotransferase (ALT, SGPT) and aspartate aminotransferase (AST, SGOT) are sensitive indicators of hepatic parenchymal cell injury. AST is present in both the cytoplasm of liver parenchymal cells and in their mitochondria. ALT is primarily a cytoplasmic enzyme and a more sensitive marker of hepatocyte injury than AST. Cardiac and skeletal muscle disorders can also cause these enzymes to be released into the serum. The PT is dependent on the production of adequate levels of procoagulant proteins by the liver: factor VII, prothrombin (II), X, V, and fibrinogen. Factor VII has a half-life of only a few hours and requires a higher rate of hepatic synthesis than the other procoagulant proteins made by the liver. Hepatic parenchymal cells probably also produce all the other procoagulant proteins except for von Willebrand s factor. We approached the problem of measuring hepatic insult in several ways. For the frequency analysis, laboratory abnormalities were considered to exist if any of the previously mentioned laboratory values had a postoperative value greater than four times the upper limit of normal. Values at four times top normal represent severe laboratory abnormalities. For purposes of comparison, another criterion for abnormality, two times top normal, was also studied. That the two criteria lead to identification of different risk factors in some cases is interesting. The less stringent criterion (2 top normal) tended to favor the less liver-specific risk factors of renal failure and diabetes, whereas the more stringent criterion (4 top normal) identified the more liver-specific variable of history of hepatitis. We hypothesize that the more severe abnormalities in laboratory values are more specific to liver function, whereas the milder abnormalities are less specific in origin. In addition to the categorical analyses, which provided aggregate data about overall laboratory abnormalities, we performed analyses on the individual laboratory variables given as continuous data. Information about the scale of a variable s change is available from continuous data in a way that it is not from categorical data. To explore the way postoperative enzyme levels scale with the risk factors, we subjected the data to multiple linear regression analysis. We used stepwise regression for the first pass and then rebuilt the models by hand with variables identified in the stepwise selection. This was done to minimize the influence of the tremendous multicollinearity that existed between the laboratory measures. For the variables AST, alkaline phosphatase, PT, and PTT, we found that each variable s baseline value was the strongest predictor, and that Fig. 5. Depiction of linear regression equation shown in Table IV for PTT. Solid line represents relationship between preoperative and postoperative variables for type I, III, IV, and descending thoracic aneurysms. Line with short dashes represents this relationship for type II aneurysms without visceral perfusion. Long-dashed line represents relationship in type II patients who received visceral perfusion during operation. Type II aneurysm extent is associated with upward shift in postoperative variable values, whereas use of visceral perfusion brings relationship back to essentially that of other aneurysm types. type II aneurysm and the use of visceral perfusion were the most important predictors of postoperative value (Table IV). We noted in the Methods section that visceral perfusion was evaluated only in type II aneurysms for the contingency table analyses, whereas it was evaluated across the entire population for the linear regression analyses. The reason for the difference is the following. In the contingency tables, the association of visceral perfusion with laboratory abnormalities would be confounded with the effect of type II aneurysm, which has a strong association with laboratory abnormalities, because visceral perfusion was not used in any other aneurysm types. Therefore, it would be impossible to evaluate the effect of visceral perfusion if the denominator for the comparison contained lower-risk aneurysm types for which it would never be used. In the regression analyses, on the other hand, because indicator variables are used to describe the effects of visceral perfusion, aneurysms that do not use this perfusion type do not contribute information. When solving the equations using the linear regression formulas, the visceral perfusion coefficients should only be subtracted from equations that also contain the type II aneurysm term.

8 152 Safi et al. January 1998 Our analysis of liver function related laboratory tests indicates that history of hepatitis, as a marker for preexisting liver disease, and type II aneurysm extent, acute rupture, and emergency presentation, as markers of ischemia, are risk factors for hepatic injury after thoracoabdominal aortic repair. Use of visceral perfusion during type II aneurysm surgery effectively negates the rise in postoperative laboratory values associated with type II aneurysm repairs performed with the simple cross-clamp technique. Special thanks to our editor, Amy Wirtz Newland. REFERENCES 1. Bynum TE, Boitnott JK, Maddrey WC. Ischemic hepatitis. Dig Dis Sci 1979;24: Cassidy WM, Reynolds TB. Serum lactic dehydrogenase in the differential diagnosis of acute hepatocellular injury. J Clin Gastroenterol 1994;19: Gitlin N, Serio KM. Ischemic hepatitis: widening horizons. Am J Gastroenterol 1992;87: Kamiyama T, Miyakawa H, Tajiri K, Marumo F, Sato C. Ischemic hepatitis in cirrhosis: clinical features and prognostic implications. J Clin Gastroenterol 1996;22: Safi HJ, Bartoli S, Hess KR, Shenaq SS, Viets JR, Butt GR, et al. Neurologic deficit in patients at high risk with thoracoabdominal aortic aneurysms: the role of cerebral spinal fluid drainage and distal aortic perfusion. J Vasc Surg 1994;20: Safi HJ, Hess KR, Randel M, Iliopoulos DC, Baldwin JC, Mootha RK, et al. Cerebrospinal fluid drainage and distal aortic perfusion: reducing neurologic complications in repair of thoracoabdominal aortic aneurysm types I and II. J Vasc Surg 1996;23: Safi HJ, Harlin SA, Miller CC, Iliopoulos DC, Joshi A, Mohasci TG, et al. Predictive factors for acute renal failure in thoracic and thoracoabdominal aortic aneurysm surgery. J Vasc Surg 1996;24: Svensson LG, Hess KR, Coselli JS, Safi HJ, Crawford ES. A prospective study of respiratory failure after high-risk surgery on the thoracoabdominal aorta. J Vasc Surg 1991;14: Svensson LG, Crawford ES, Hess KR, Coselli JS, Safi HJ. Experience with 1509 patients undergoing thoracoabdominal aortic operations. J Vasc Surg 1993;17: Safi HJ. Long-term results following thoracoabdominal aortic aneurysm repair. In: Branchereau A, Jacobs M, editors. Long-term results of arterial interventions. Marseille: Arnette Blackwell SA, 1997: Submitted Feb. 25, 1997; accepted Sep. 3, DISCUSSION Dr. James M. Seeger (Gainesville, Fla.). Thoracoabdominal aortic aneurysm repair is associated with significant morbidity and mortality rates, and the necessary visceral ischemia that is part of this procedure appears to be an important risk factor for postoperative organ injury. Pulmonary, renal, hematopoietic, and hepatic dysfunction are common after thoracoabdominal aortic aneurysm repair, usually occurring together, and multiorgan system failure is the most common cause of death, at least in our current series at the University of Florida. In addition, the duration of visceral ischemia has been found to be a significant predictor for organ dysfunction and death, and the mechanism by which visceral ischemia includes both local and distant organ injury after thoracoabdominal aortic aneurysm repair, appears to be in part from activation and release of proinflammatory cytokines upon reperfusion of the ischemic viscera. The study presented today has focused on hepatic injury after thoracoabdominal aortic aneurysm repair and demonstrated type II thoracoabdominal aortic aneurysm repair, a history of hepatitis, emergency repair, and rupture to be risk factors for significant liver enzyme elevation after thoracoabdominal aortic aneurysm repair. In addition, visceral perfusion using left atrial femoral bypass during type II thoracoabdominal aortic aneurysm repair was shown to be somewhat protective for hepatic ischemia, although to a lesser degree than one might expect. These observations are similar to those of a recently presented study of a smaller number of patients from our group, in which left atrial femoral bypass was shown to decrease hepatic as well as other organ injury after thoracoabdominal aortic aneurysm repair and to significantly limit the systemic release of proinflammatory cytokines. These observations lend increasing support to the hypothesis that limiting the duration of visceral ischemia during thoracoabdominal aortic aneurysm repair, modulating the local and systemic inflammatory response that is a consequence of visceral ischemia/reperfusion, or both of these will result in decreased morbidity rates and improved survival rates after thoracoabdominal aortic aneurysm repair. I have four questions for the authors. First, what was the average visceral ischemia time in patients who underwent type II thoracoabdominal aortic aneurysm repair with and without left atrial femoral bypass? Was there any relationship that you observed between the duration of visceral ischemia and hepatic or other organ injury? Second, were any of the preoperative hepatic laboratory values more or less specific in predicting liver dysfunction after operation? We have had significant difficulty in determining who really has preoperative hepatic dysfunction

9 Volume 27, Number 1 Safi et al. 153 that is of importance. Third, was there a relationship between hepatic injury and other organ dysfunction or multiple organ dysfunction in your series? Finally, was left atrial femoral bypass significantly protective in patients who had preoperative hepatic dysfunction or cirrhosis to allow thoracoabdominal aortic aneurysm repair to be performed safely? We found hepatic dysfunction to be a particularly significant predictor of death after both thoracoabdominal aortic aneurysm repair and infrarenal abdominal aortic aneurysm repair, even so that we are now quite wary of performing aortic surgery in patients who have cirrhosis or severe hepatic dysfunction. Dr. George V. Letsou. Thank you very much, Dr. Seeger, for your comments. We also found that preoperative liver dysfunction was a very significant predictor of postoperative hepatic dysfunction. In a multivariate analysis that we did not present here, the most important predictor of postoperative hepatic dysfunction is preoperative hepatic dysfunction, especially the preoperative alkaline phosphatase level, and in a multivariate analysis the preoperative liver status accounts for about 87% of the risk and the type of aneurysm or extent of aneurysm accounts for about 20% of the risk. If visceral perfusion is used, it can decrease the risk by approximately 20%. The overwhelming predictor of postoperative dysfunction, as you point out, is preoperative liver dysfunction. There was no more relation between the visceral ischemic time and the incidence of hepatic dysfunction in our series. I believe your other question related to the relationship between hepatic dysfunction and multisystem organ failure. We did not analyze for multisystem organ failure in this series but just for death, so it would be difficult to address the question of multisystem organ failure in that fashion, although our experience, I think, would be similar to yours in that most of the patients who die do so of multisystem organ failure. Dr. Richard P. Cambria (Boston, Mass.). Dr. Letsou, congratulations on a nice presentation. In the December 1996 issue of the Journal of Vascular Surgery, we presented similar data looking at a more in-depth profile of coagulation factors and their relationship to hepatic and visceral ischemia (1996;24:936-45). Most have correlated visceral ischemic problems with the threat of perioperative coagulopathy. I may have missed it in your presentation, but what was the relationship, if any, in your series between visceral ischemia, liver function abnormalities, and perioperative bleeding? Dr. Letsou. We didn t address perioperative bleeding in this study, but when we assessed for liver function, we looked at both preoperative and postoperative values for PT, PTT, fibrinogen, alkaline phosphatase, AST, ALT, and perhaps one or two others that I am missing. Of those factors, preoperative elevations in alkaline phosphatase were the most important predictor of postoperative hepatic problems. The PT, PTT, and fibrinogen also were statistically significant, whereas AST and ALT were not predictors of postoperative hepatic dysfunction. Dr. Bruce J. Gewertz (Chicago, Ill.). I also very much enjoyed the paper and am aware of the terrific work you do in this area. I am a little confused. If there was no correlation between the time of intraoperative ischemia and liver dysfunction, what is the mechanism for the liver dysfunction, and why would it necessarily be associated with type II thoracoabdominal aortic aneurysms? Do you have any thoughts about the mechanism? Dr. Letsou. Well, I think that the objective is to minimize ischemic time. I believe one of the reasons there was no correlation in ischemic time is that the policy regarding hepatic and visceral perfusion changed with time over the course of the series from 1991 to Before 1992 most patients were selectively perfused. After that time, it was used as a pretty routine standard procedure in patients who had type II extensive aneurysms. As a consequence, the number of patients who had significant ischemic times were mostly in the early part of the study and there are not as many of them. I believe that is one reason that ischemic time is not a significant factor. We do believe that minimizing the ischemic time, which is the overall objective of this technique, is an extremely important factor in minimizing hepatic dysfunction and probably the explanation for why there is less hepatic dysfunction. Dr. W. Andrew Oldenburg (Jacksonville, Fla.). You looked at aneurysm types, but did you also look at the amount of visceral occlusive disease to begin with per type? Dr. Letsou. No, we did not look at the amount of visceral occlusive disease. Dr. Oldenburg. Do you think that may have made a difference? Dr. Letsou. I think that most of the patients have a significant amount of visceral occlusive disease; it is probably present in about 60% to 80% of the patients. The number of patients who do not have it, I think, would be small and possibly would throw off the statistics, but I think that probably is a very important factor. Dr. Calvin B. Ernst (Ann Arbor, Mich.). It has been suggested that patients with thoracoabdominal aneurysms in whom postoperative multiorgan system failure develops may have significant pancreatic ischemia with a resultant release of proinflammatory cytokines from the ischemic pancreas. Did you look at pancreatic ischemia and the various enzymes as such ischemia relates to the coagulopathy after thoracoabdominal aortic aneurysm repair? Dr. Letsou. We have a study to look at the pancreatic function after operation, but we did not look at it for this study, so I don t think I can really comment on that.